Use of estrogen compounds to increase libido in women

ABSTRACT

Disclosed is a method of increasing libido in a woman, said method comprising administering to said woman an effective amount of an estrogenic component selected from the group consisting of: substances represented by the following formula (I) in which formula R 1 , R 2 , R 3 , R 4  independently are a hydrogen atom, a hydroxyl group or an alkoxy group with 1-5 carbon atoms; each of R 5 , R 6 , R 7  is a hydroxyl group; no more than 3 of R 1 , R 2 , R 3 , R 4  are hydrogen atoms; precursors capable of liberating a substance according to the aforementioned formula when used in the present method; and mixtures of one or more of the aforementioned substances and/or precursors.

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to a method of increasing libido ina woman, said method comprising administering an effective amount of anestrogenic component to said woman

BACKGROUND OF THE INVENTION

[0002] The presence of a normal libido, defined as the urge to engage insexual activity and intercourse, is an important component of anindividual's well-being. Low or decreased libido is a common complaintin women. Such complaints are observed in pre peri- as well aspost-menopausal women.

[0003] A low libido is characterised by a lack of interest in sexualintercourse and/or the lack of ability to achieve orgasm. A decreasedlibido may be accompanied by a decrease in intensity of orgasm. It isimportant to note that a decrease in libido is often associated with aprofound sense of loss of a once normal and active interest in sexualactivity.

[0004] U.S. Pat. No. 6,284,263 (Place) is concerned with a method oftreating sexual dysfunction in female individuals, comprising bucallyadministering a therapeutically effective amount of an androgenic agent,a progestin and an estrogen. The US-patent specifically mentions thefollowing estrogens: 17α-estradiol, 17β-estradiol, ethinyl estradiol,pharmaceutically acceptable esters and ethers of 17α-estradiol,17β-estradiol and ethinyl estradiol, estriol, estriol succinate,polyestrol phosphate, estrone, estrone acetate, estrone sulfate,piperazine estrone sulfate, quinestrol, mestranol and conjugated equineestrogens. As explained in the US-patent, vaginal atrophy anddyspareunia are a common cause of sexual dysfunction.

[0005] In an article by Grio et al., Minerva Ginecol, “Sexuality inmenopause. Importance of adequate replacement therapy” (1999), 51(3),59-62, it is observed that estrogen deficiency in menopause isresponsible for reduced libido and uncomfortable trophic disorders ofthe urogenital tract leading to reduced vaginal lubrication and severealterations affecting sexual function. The authors treated 102menopausal patients who presented reduced libido and orgasmicdifficulties, as well as other menopausal problems, with 1 7-β estradioland norethisterone acetate using a transdermal route. It is noted in thearticle that the main advantage offered by the transdermal route is thatestrogens bypass the liver and reach the target organs in an unmodifiedmanner. The authors conclude that the use of 17-β estradiol andnorethisterone acetate can effectively modify menopausal symptoms,improving both quality of life and sexual function.

[0006] Well-known estrogens, in particular biogenic estrogens (i.e.estrogens that occur naturally in the human body), are eliminated fromthe blood stream very quickly. For instance, for the main human biogenicestrogen 17β-estradiol the half-life is around 1 hour. As a result,between separate administration events, blood serum levels of suchbiogenic estrogens tend to fluctuate considerably. Thus, shortly afteradministration, the serum concentration is usually several times higherthan the optimum concentration. In addition, if the next administrationevent is delayed, serum concentrations will quickly decrease to a levelwhere the estrogen is no longer physiologically active.

[0007] The most important synthetically altered estrogenic steroid is17α-ethinyl estradiol (EE). This estrogen is dominant in oral hormonalcontraception. Apart from EE, mestranol has been used in a few cases;mestranol is a “prodrug” that is metabolised to EE in the organism. Theliver is a target organ for estrogens. The secretion activity that isaffected by estrogens in the human liver includes increased synthesis oftransport proteins CBG, SHBG, TBG, several factors that are importantfor the physiology of blood clotting, and lipoproteins. The stronghepatic estrogenicity of ethinyl estradiol and diethylstilbestrol (DES),especially their effect on haemostasis factors, may explain why thesesynthetic estrogens have been associated with the enhanced risk ofthromboembolism. Other undesirable side-effects that have been reportedin relation to the use of synthetic estrogens include, fluid retention,nausea, bloating, chlolelithiasis, headache, breast pain and an enhancedrisk of breast cancer with longer term usage.

[0008] The aforementioned deficits are of considerable clinicalsignificance when commonly known biogenic or synthetic estrogens areapplied. Consequently, there is an as yet unmet need for estrogens thatdo not display these deficits and which can suitably be employed in amethod of increasing libido in women.

SUMMARY OF THE INTENTION

[0009] The inventors have unexpectedly found that a special group ofestrogenic substances do not exhibit the aforementioned drawbacks andcan be used very effectively to improve libido in women. Theseestrogenic substances are represented by the following formula

[0010] in which formula R₁, R₂, R₃, R₄ independently are a hydrogenatom, a hydroxyl group or an alkoxy group with 1-5 carbon atoms; each ofR₅, R₆, R₇ is a hydroxyl group; no more than 3 of R₁, R₂, R₃, R₄ arehydrogen atoms.

[0011] These estrogens are different from the estrogens commonly appliedin estrogen replacement therapy, i.e. ethinyl estradiol, estradiol andits esters such as the acetate, valerate or benzoate, mestranol, theconjugated equine estrogens and estrone sulfate.

[0012] A known representative of this group of estrogenic substances is1,3,5 (10)-estratrien-3, 15α,16α,17β-tetrol, also known by the names ofestetrol, oestetrol and 15α-hydroxyestriol. Estetrol is an estrogen thatis produced by the fetal liver during human pregnancy. Unconjugatedestetrol levels in maternal plasma peak at about 1.2 ng/ml at termpregnancy and are about 12 times higher in fetal than in maternal plasma(Tulchinsky et al., 1975. J. Clin. Endocrinol. Metab., 40, 560-567).

[0013] In 1970, Fishman et al., “Fate of 15α-hydroxyestriol-³H in AdultMan”, J Clin Endocrinol Metab (1970) 31, 436-438, reported the resultsof a study wherein tritium labeled 15α-hydroxyestriol (estetrol) wasadministered intravenously to two adult women. It was found that theestetrol was rapidly and completely excreted in urine as theglucosiduronate and that virtually no metabolism except for conjugationtook place.

[0014] Between 1975 and 1985 several researchers have investigated theproperties of estetrol and reported on its estrogenic potency anduterotrophic activity. The most relevant publications that were issuedduring this period are mentioned below:

[0015] Levine et al., 1984. Uterine vascular effects of estetrol innonpregnant ewes. Am. J. Obstet. Gynecol. 148:73, 735-738: “Whenintravenously administered in nonpregnant ewes, estetrol is 15 to 30times less potent than estriol and 17β-estradiol in uterinevasodilation”.

[0016] Jozan et al., 1981. Different effects of oestradiol, oestriol,oestetrol and of oestrone on human breast cancer cells (MCF-7) in longterm tissue culture. Acta Endocrinologica, 98, 73-80: “Estetrolagonistic potency is 2% of the magnitude observed for 17β-estradiol inin vitro cell proliferation”.

[0017] Holinka et al., 1980. Comparison of effects of estetrol andtamoxifen with those of estriol and estradiol on the immature ratuterus. Biol. Reprod. 22, 913-926: “Subcutaneously administered estetrolhas very weak uterotrophic activity and is considerable less potent than17β-estradiol and estriol”.

[0018] Holinka et al., 1979. In vivo effects of estetrol on the immaturerat uterus. Biol. Reprod. 20, 242-246: “Subcutaneously administeredestetrol has very weak uterotrophic activity and is considerable lesspotent than 17β-estradiol and estriol”.

[0019] Tseng et al., 1978. Heterogeneity of saturable estradiol bindingsites in nuclei of human endometrium. Estetrol studies. J. SteroidBiochem. 9, 1145-1148: “Relative binding of estetrol to estrogenreceptors in the human endometrium is 1.5% of 17β-estradiol”.

[0020] Martucci et al., 1977. Direction of estradiol metabolism as acontrol of its hormonal action-uterotrophic activity of estradiolmetabolites. Endocrin. 101, 1709-1715: “Continuous administration ofestetrol from a subcutaneous depot shows very weak uterotrophic activityand is considerably less potent than 17β-estradiol and estriol”. Tsenget al., 1976. Competition of estetrol and ethynylestradiol withestradiol for nuclear binding in human endometrium. J. Steroid Biochem.7, 817-822: “The relative binding constant of estetrol binding to theestrogen receptor in the human endometrium is 6.25% compared to17β-estradiol (100%)”.

[0021] Martucci et al., 1976.,Uterine estrogen receptor binding ofcatecholestrogens and of estetrol(1,3,5(10)-estratriene-3,15alpha,16alpha, 17beta-tetrol). Steroids, 27,325-333: “Relative binding affinity of estetrol to rat uterine cytosolestrogen receptor is 0.5% of 17β-estradiol (100%). Furthermore, therelative binding affinity of estetrol to rat uterine nuclear estrogenreceptor is 0.3% of 17β-estradiol (100%)”.

[0022] All of the above publications have in common that the authorshave investigated the estrogenic potency of estetrol. Without exceptionthey all conclude that estetrol is a weak estrogen. In some of the citedarticles the estrogenic potency of estetrol has been found to be lowerthan that of another biogenic estrogen, namely, 17β-estradiol, which isconsidered to be a relatively weak estrogen (e.g. compared to ethinylestradiol). With these findings in mind, it is not surprising that theinterest in estetrol has dwindled since the early eighties and that nopublications on the properties of estetrol have been issued since.

[0023] U.S. Pat. No. 5,468,736 (Hodgen) describes a method of hormonereplacement therapy involving the administration of estrogen togetherwith an amount of antiprogestin (antiprogestogen), which inhibitsestrogen-induced endometrial proliferation in women. In Example 3 thecombined use of estetrol and lilopristone is mentioned. No clues aregiven in the examples as to the mode and frequency of administration orregarding the dosage level employed. A disadvantage associated with theuse of antiprogestogens, such as lilopristone, is the risk of inducingabnormal endometrial morphology, i.e. cystic hyperplasia, as has beenobserved in women who received an antiprogestogen treatment againstendometriosis (Murphy et al., 1995. Fertil. Steril., 95, 761-766).Furthermore it is noted that antiprogestogens are a well-known abortiveagent and consequently should not be used by women at a fertile age whowish to conceive. The benefits of the present invention may be realisedwithout the application of an antiprogestogen.

[0024] In view of the low estrogenic potency of the estetrol-likesubstances that are employed in accordance with the invention, it issurprising that these substances can effectively be used in the presentmethod. Although the inventors do not wish to be bound by theory, it isbelieved that the unexpected efficacy of enterally or parenterallyadministered estetrol-like substances results from the combination ofunforeseen favourable pharmacokinetic (ADME) and pharmacodynamicproperties of these substances.

[0025] As regards the pharmacokinetic properties of the presentestrogenic substances the inventors have discovered that their in vivohalf-life is considerably longer than that of other. biogenic estrogens.Thus, even though estetrol and estetrol-like substances have relativelylow estrogenic potency, they may effectively be employed in the presentmethod because their low potency is compensated for by a relatively highmetabolic stability, as demonstrated by a long half-life.

[0026] In addition, it is believed that the unexpected efficacy of thepresent estetrol-like substances may be explained by the relatively highaffinity for the estrogen receptor α (ERα) as compared to the estrogenreceptor β (ERβ). The latter characteristic is an unique feature of theestrogenic substances employed in the present method. The relativelyhigh affinity of the present estrogenic substances for the ERα receptor,or conversely the relatively low affinity for the ERβ receptor, isbelieved to be somehow associated with the high efficacy of the presentsubstances as libido enhancers.

[0027] Recent publications strongly suggest that the ERα gene expressionplays a key role in sexual behaviour of mammals. Ogawa et al., “Roles ofEstrogen Receptor-α Gene Expression in Reproduction-Related Behaviors inFemale Mice”, Endocrinology (1998), 139, 5070-81 report the results ofstudies into the sexual behavior of estrogen receptor knockout (ERKO)mice. It was found that gonadectomised female ERKO mice that weredeficient specifically for the ERα, but not for the ERβ, gene, did notshow any lordosis response to the treatment with estrogen or estrogenplus progesterone.

[0028] Another study by the same authors (Ogawa et al., “Survival ofreproductive behaviors in estrogen receptor β gene-deficient (βERKO)male and female mice”, Neurobiology (1999), 96, 12887-92, was conductedin estrogen receptor β gene-deficient (βERKO) male and female mice. Itwas found that females lacking a functional β isoform of the ER geneshowed normal lordosis and courtship behaviors. According to the authorsthese results highlight the importance of ERα for the normal expressionof natural reproductive behaviors.

[0029] In summary, although the mechanisms by which the presentestrogenic substances exert their favourable effect are not fullyunderstood, it is evident that these substances differ from otherbiogenic estrogens in 2 important aspects. Firstly the presentestrogenic substances exhibit a surprisingly long in vivo half-life.Secondly the ratio between the affinity of these substances for the ERαand the ERβ receptor is much higher than that of other known (biogenic)estrogens.

[0030] Another advantageous property of the present estrogenicsubstances resides in the fact that sex hormone-binding globulin (SHBG)hardly binds these estrogenic substances, meaning that, in contrast tomost known estrogens, serum levels are representative for bio-activityand independent of SHBG levels. In addition, this means that the impactof an administered dosage, particularly in case such an administrationconstitutes an isolated event, is not suppressed as a result ofinactivation by SHBG-binding.

[0031] A further benefit of the present estrogenic substances is derivedfrom their relative insensitivity to interactions with other drugs(drug-drug interactions). It is well known that certain drugs maydecrease the effectiveness of estrogens, such as ethinyl estradiol, andother drugs may enhance their activity, resulting in possibly increasedside-effects. Similarly estrogens may interfere with the metabolism ofother drugs. In general, the effect of other drugs on estrogens is dueto interference with the absorption, metabolism or excretion of theseestrogens, whereas the effect of estrogens on other drugs is due tocompetition for metabolic pathways.

[0032] The clinically most significant group of estrogen-druginteractions occurs with drugs that may induce hepatic microsomalenzymes which may decrease estrogen plasma levels below therapeuticlevel (for example, anticonvulsant agents; phenytoin, primidone,barbiturates, carbamazepine, ethosuximide, and methosuximide;antituberculous drugs such as rifampin; antifungal drugs such asgriseofulvin). The present estrogenic substances are less dependent onup- and downregulation of microsomal liver enzymes (e.g. P450's) andalso are less sensitive to competition with other P450 substrates.Similarly, they do not interfere significantly in the metabolism ofother drugs.

[0033] The conjugates of most estrogens, as formed in the liver, areexcreted in the bile and may be broken down by gut bacteria in the colonto liberate the active hormone which can then be reabsorbed(enterohepatic recirculation). There are clinical reports that supportthe view that enterohepatic recirculation of estrogens decreases inwomen taking antibiotics such as ampicillin, tetracycline, etc.Conjugated forms of the present estrogenic substances are hardlyexcreted in the bile, meaning that they are substantially insensitive todrugs that do influence the enterohepatic recirculation of otherestrogens.

[0034] The above observations serve to explain why the estrogenicsubstances of the invention can advantageously be used in a method ofincreasing libido in women. The present estrogenic substances exhibit asurprisingly long in vivo half-life in combination with a relativelyhigh affinitiy for the ERα receptor which is believed to play a crucialrole in sexual behaviour. In addition, the present estrogenic substanceshardly suffer from drug-drug interactions and thus produce a veryconsistent, i.e. predictable, impact. Thus, the efficacy of theestrogenic substances of the invention is highly reliable.

DETAILED DESCRIPTION OF THE INVENTION

[0035] Accordingly, the present invention is specifically concerned witha method of increasing libido in a woman which comprises administeringto said woman an effective amount of an estrogenic component selectedfrom the group consisting of:

[0036] substances represented by the following formula

[0037] in which formula R₁, R₂, R₃, R₄ independently are a hydrogenatom, a hydroxyl group or an alkoxy group with 1-5 carbon atoms; each ofR₅, R₆, R₇ is a hydroxyl group;; no more than 3 of R₁, R₂, R₃, R₄ arehydrogen atoms;

[0038] precursors capable of liberating a substance according to theaforementioned formula when used in the present method; and

[0039] mixtures of one or more of the aforementioned substances and/orprecursors.

[0040] The term “estrogenic component” as used throughout this documentencompass substances that are capable of triggering an estrogenicresponse in vivo, as well as precursors that are capable of liberatingsuch an estrogenic component in vivo when used in accordance with thepresent invention. In order for estrogenic components to trigger such aresponse they normally have to bind to an estrogen receptor, whichreceptors are found in various tissues within the mammalian body.

[0041] It is noted that the present invention not only encompasses theuse of estrogenic components specifically mentioned in this application,but also metabolites of these hormones that display comparable in vivofunctionality. In this context it is observed that, for instance,estriol is a metabolite of 17beta-estradiol. The term “estrogenicsubstances” as used in this document does not encompass tritium (³H)labeled estrogenic substances such as tritium labeled estetrol.

[0042] The present estrogenic substances are distinct from both thebiogenic and synthetic estrogens that are commonly applied inpharmaceutical formulations in that they contain at least 4 hydroxylgroups. The present substances are special in that the 5 membered ringin the steroid skeleton comprises 3 hydroxyl substituents rather than0-2.

[0043] Known estrogens that contain at least 4-hydroxyl groups andderivatives thereof are:

[0044] 1,3,5(10)-estratrien-2,3,15α,16α,17β-pentol 2-methyl ether

[0045] 1,3,5(10)-estratrien-2,3,15β,16α,17β-pentol 2-methyl ether

[0046] 1,3,5(10)-estratrien-2,3,16α,17β-tetrol

[0047] 1,3,5(10)-estratrien-3,4,16α,17β-tetrol 4-methyl ether

[0048] 1,3,5(10)-estratrien-3,15α,16α,17β-tetrol

[0049] 1,3,5(10)-estratrien-3,15α,16α,17β-tetrol tetra acetate

[0050] 1,3,5(10)-estratrien-3,15β,16β,17β-tetrol tetra acetate

[0051] Preferably, the estrogenic substance applied as the activecomponent in the present composition is a so called biogenic estrogen,i.e. an estrogen that occurs naturally in the human body, a precursor ofa biogenic estrogen or mixtures thereof. Because biogenic estrogens arenaturally present in the fetal and female body, side-effects are notexpected to occur, particularly not if the serum levels resulting fromthe exogenous administration of such estrogens do not substantiallyexceed naturally occurring concentrations. Since estetrol serum levelsin the fetus are several times higher than those found in pregnantfemales and knowing that the fetus is particularly vulnerable, estetrolis deemed to be a particularly safe biogenic estrogen. Side-effects arenot expected to occur, particularly not if the serum levels resultingfrom the exogenous administration of such estrogens do not substantiallyexceed naturally occurring (fetal) concentrations. With syntheticestrogens such as ethinyl estradiol there is a (dose dependent) risk ofundesirable side-effects, such as thromboembolism, fluid retention,nausea, bloating, cholelithiasis, headache, breast pain and an enhancedrisk of breast cancer with longer term usage.

[0052] In a preferred embodiment of the present invention the estrogenicsubstance contains 4 hydroxyl groups. Also, in the aforementionedformula, R₁ preferably represents a hydrogen atom. In said formulapreferably at least 2, more preferably at least 3 of the groups R₁, R₂,R₃ and R₄ represent a hydrogen atom.

[0053] The estrogenic substances according to the formula encompassvarious enantiomers since the carbon atoms that carryhydroxyl-substituents R₅, R₆ and R₇ are chirally active. In onepreferred embodiment, the present estrogenic substance is 15α-hydroxysubstituted. In another preferred embodiment the substance is16α-hydroxy substituted. In yet another preferred embodiment, thesubstances is 17β-hydroxy substituted. Most preferably the estrogenicsubstances are 15α,16α,17β-trihydroxy substituted.

[0054] In another preferred embodiment of the present invention R₃represents a hydroxyl group or an alkoxy group. In another preferredembodiment the groups R₁, R₂ and R₄ represent hydrogen atoms, in whichcase, if R₃, R₅, R₆ and R₇ are hydroxyl groups, the substance is1,3,5(10)-estratrien-3,15,16,17-tetrol. A preferred isomer of the lattersubstance is 1,3,5(10)-estratrien-3,15α,16α,17β-tetrol (estetrol).

[0055] The invention also encompasses the use of precursors of theestrogenic substances that constitute the active component in thepresent method. These precursors are capable of liberating theaforementioned estrogenic substances when used in the present method,e.g. as a result of metabolic conversion. These precursors arepreferably selected from the group of androgenic precursors as well asderivatives of the present estrogenic substances. Suitable examples ofandrogenic precursors include androgens that can be converted into thepresent estrogenic substances through i*t vivo aromatisation. Examplesof derivatives of the present estrogenic substances that can suitably beused as precursors include such substances wherein the hydrogen atom ofat least one of the hydroxyl groups has been substituted by an acylradical of a hydrocarbon carboxylic, sulfonic acid or sulfamic acid of1-25 carbon atoms; tetrahydrofuranyl; tetrahydropyranal; or a straightor branched chain glycosidic residue containing 1-20 glycosidic unitsper residue.

[0056] Typical examples of precursors which can suitably be used inaccordance with the invention are esters that can be obtained byreacting the hydroxyl groups of the estrogenic substances withsubstances that contain one or more carboxy (M⁺ ⁻OC—) groups, wherein M⁺represents a hydrogen or (akali)metal cation. Hence, in a particularlypreferred embodiment, the precursors are derivatives of the estrogenicsubstances, wherein the hydrogen atom of at least one of the hydroxylgroups in said formula has been substituted by —CO—R, wherein R is ahydrocarbon radical comprising from 1-25 carbon atoms. Preferably R ishydrogen, or an alkyl, alkenyl or aryl radical comprising from 1-20carbon atoms.

[0057] The present method encompasses protocols wherein the estrogeniccomponent is administered at predetermined, regular intervals as well asa protocol wherein the estrogenic component is administered on demand atthe moment a woman wishes to increase her libido.

[0058] The term “libido” has been defined above as the urge to engage insexual activity and intercourse. It is noted that such an urge may beaffected by both psychological and fysiological factors (e.g. vaginalatrophy and dyspareunia). In a particularly preferred embodiment of theinvention the present method is employed to increase the libido of afemale who does not suffer from decreased libido as a result of vaginalatrophy and/or dyspareunia.

[0059] The present method may suitably employ enteral or parenteraladministration of the estrogenic component. The term “parenteraladministration” as used in here encompasses transdermal, intranasal,intravaginal, pulmonary, buccal, subcutaneous, intramuscular andintrauterine administration. The term “enteral administration” includesoral as well as rectal administration.

[0060] Preferably the mode of administration is selected from the groupconsisting of oral, transdermal, intranasal, intravaginal, pulmonary,rectal, buccal, subcutaneous, intramuscular or intra-uterineadministration. More preferably the mode of administration is selectedfrom the group consisting of oral, transdermal, subcutaneous,intramuscular, intranasal, pulmonary and vaginal administration. In aparticularly preferred embodiment the present method employs oral,intranasal, intravaginal or rectal administration. Even more preferablythe present method employs oral or intranasal administration.

[0061] Oral, intranasal, rectal, buccal and pulmonary administration areideally suited for (at least) once daily administration. Transdermaladministration is advantageously applied at frequencies between once aday and once a month. Intravaginal and intrauterine administrations areadvantageously operated at administration frequencies between onceweekly and once monthly. Subcutaneous and intramuscular administrationare suitably done in the form of depot injections at intervals of 1 weekto 6 months, preferably at intervals of 4 weeks to 3 months.

[0062] For reasons of convenience and also to achieve high compliancerates, the present method preferably utilises administration intervalsof 1 day, 1 week or 1 month. Regimens that employ once daily oral orintranasal administration, once weekly transdermal or once monthlyintravaginal or subcutaneous administration are particularly preferred.

[0063] Irrespective of the mode of administration, the estrogeniccomponent is preferably administered in an amount effective to achieve ablood serum concentration of at least 1 nanogram per litre, morepreferably of at least 10 nanogram per litre, most preferably at least100 nanogram per litre. Generally the resulting blood serumconcentration of the estrogenic component will not exceed 100 μg perlitre, preferably it will not exceed 50 μg per litre, more preferably itwill not exceed 25 μg per litre.

[0064] In accordance with the present method the estrogenic component isusually administered in an amount of less than 1 mg per kg of bodyweightper day preferably of less than 0.4 mg per kg of bodyweight per day. Inorder to achieve a significant impact from the administration of theestrogenic component, it is advisable to administer in an amount of atleast 1 μg per kg of bodyweight per day. Preferably, the administeredamount is at least 5 μg per kg of bodyweight per day.

[0065] Oral administration of the active component is preferably done inan amount of less than 400 μg per kg of bodyweight per day, preferablyof less than 200 μg per kg of bodyweight per day. In order to achieve asignificant impact from the administration of the active component, itis advisable to orally administer in an amount of at least 2 μg per kgof bodyweight per day. Preferably, the orally administered amount is atleast 5 μg per kg of bodyweight per day.

[0066] The present method comprises administering to a woman in need ofenhanced libido an effective amount of the present estrogenic component.The amounts needed to be effective will differ from individual toindividual and are determined by factors such as the individual'sendogenous estrogen levels, body weight, route of administration and theefficacy of the particular estrogen substance used. Suitably, in thepresent method, the estrogenic component is administered in an dosage ofat least 0.05 mg per day, preferably of at least 0.1 mg per day. Themaximum dosage normally does not exceed 40 mg per day, preferably itdoes no exceed 20 mg per day.

[0067] The present method is particularly suited for increasing libidoin hypoestrogenic women. A typical example of hypoestrogenic women aremenopausal and postmenopausal females. It is noted that many menopausaland postmenopausal women undergo estrogen replacement therapy, whichusually involves the combined administration of an estrogen (often 17-βestradiol) and a progestogen. Since 17-β estradiol is deemed to be lesseffective in restoring libido than the present estrogenic substances, itis deemed advantageous to administer these estrogenic substances, inaddition to or instead of 17-β estradiol, to improve the libido ofmenopausal or postmenopausal women who are using estrogen replacementtherapy.

[0068] In a particularly preferred embodiment of the invention themethod employs oral administration of the active estrogenic component.The term oral administration as used in here also encompasses oralgavage administration. The inventors have surprisingly found that,despite its low potency, estetrol and related estrogenic substances mayadvantageously be administered orally. Although the inventors do notwish to be bound by theory, it is believed that the unexpected efficacyof orally administered estetrol-like substances results from thecombination of special pharmacokinetic and pharmacodynamic properties ofthese substances.

[0069] The inventors have discovered that the oral bioavailability ofestetrol-like substances is surprisingly high and that their in vivohalf-life is considerably longer than that of biogenic estrogens. Thus,even though estetrol and estetrol-like substances have relatively lowestrogenic potency, they may effectively be administered orally.

[0070] Another important advantage of oral administration of estetroland estetrol-like substances resides in the fact that the hepaticeffects of these substances are deemed to be minimal since they arehardly metabolised during the so called “first pass”. The first-passeffect of drugs given orally refers to the process of drug degradationby the liver during a drug's transition from initial ingestion tocirculation in the blood stream. After resorption from the intestinallumen, orally applied active ingredients enter the organism via theliver. This 0 fact is of specific importance for estrogenic agents asthe liver is a target organ for estrogens; oral intake of estrogensresults in strong estrogenic effects in the liver. Therapeuticallyequivalent doses of biogenic estrogens, when applied orally, result inclear responses of hepatic parameters, such as increase of SHBG, CBG,angiotensinogen and HDL (high density lipoprotein). These hepaticeffects of estrogens are also observed when equine estrogen formulations(so-called conjugated estrogens) are used. Ethinyl estradiol anddiethylstilbestrol (DES) have an even greater hepatic estrogenicity.Elger et al., J. Steroid Biochem. Molec., Biol. (1995), 55(3/4),395-403, have reported that EE or DES have much higher hepato-cellularthan systemic estrogenicity: in relation to FSH-secretion inhibitoryactivity these estrogens are 4-18 times more active in the liver thanestrone sulfate.

[0071] Regular administration of estrogens during prolonged periods oftime has been associated with endometrial proliferation in women. It iswidely accepted that “unopposed” estrogen therapy substantiallyincreases the risk of endometrial cancer (Cushing et al., 1998. Obstet.Gynecol.91, 35-39; Tavani et al., 1999. Drugs Aging, 14, 347-357). Inaddition, there is also evidence of a significant increase in breastcancer with long-term (10-15 years) use of estrogen therapy (Tavani etal., 1999. Drugs Aging, 14, 347-357; Pike et al., 2000. Steroids, 65,659-664).

[0072] In order to counteract any potential negative effects ofunopposed estrogen administration, particularly in case of frequentadministration (e.g. on average more than 2, particularly more than 3times a week) it is preferred to co-administer a progestogenic componentto inhibit estrogen stimulation of the endometrium (Beral et al., 1999.J. Epidemiol. Biostat., 4, 191-210) or to administer a progestogeniccomponent at least during a period of ten day at least every threemonths.

[0073] Examples of progestogenic components which may suitably be usedin accordance with the present invention include: progesterone,levonorgestrel, norgestimnate, norethisterone, dydrogesterone,drospirenone, 3-beta-hydroxydesogestrel, 3-keto desogestrel(=etonogestrel), 17-deacetyl norgestimate, 19-norprogesterone,acetoxypregnenolone, allylestrenol, anagestone, chlormadinone,cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone,dimethisterone, ethisterone, ethynodiol diacetate, flurogestone acetate,gastrinon, gestodene, gestrinone, hydroxymethylprogesterone,hydroxyprogesterone, lynestrenol (=lynoestrenol), medrogestone,medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone(=norethisterone), norethynodrel, norgestrel (includes d-norgestrel anddl-norgestrel), norgestrienone, normethisterone, progesterone,quingestanol,(17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-diene-20-yn-3-one,tibolone, trimegestone, algestone acetophenide, nestorone, promegestone,17-hydroxyprogesterone esters, 19-nor-17hydroxyprogesterone,17alpha-ethinyl-estosterone, 17alpha-ethinyl-19-nor-testosterone,d-17beta-acetoxy-13beta-ethyl-17alpha-ethinyl-gon-4-en-3-one oxime andprecursors of these compounds that are capable of liberating theseprogestogens in vivo when used in the present method. Preferably theprogestogen used in the present method is selected from the groupconsisting of progesterone, desogestrel, etonogestrel, gestodene,dienogest, levonorgestrel, norgestimate, norethisterone, drospirenone,trimegestone, dydrogesterone, precursors of these progestogens andmixtures thereof.

[0074] The progestogenic component is suitably administered in an amountwhich is equivalent to an oral dosage of 30-750 μg levonorgestrel, morepreferably of 50-400 μg levonorgestrel.

[0075] In another preferred embodiment of the invention the presentmethod employs the co-administration of the estrogenic component with anandrogenic component. It was found that in some cases the combinedadministration of an estrogenic and an androgenic component is moreeffective than the administration of the estrogenic component per se inachieving improved libido. The androgenic component may suitably beselected from the group consisting of dehydroepiandrosterone (DBEA);DHEA-sulphate; testosterone; testosterone esters such as testosteroneundecanoate, testosterone propionate, testosterone phenylpropionate,testosterone isohexanoate, testosterone enantate, testosterone bucanate,testosterone decanoate, testosterone buciclate; danazol; gestrinone;methyltestosterone; mesterolon; stanozolol; androstenedione;dihydrotestosterone; androstanediol; metenolon; fluoxymesterone;oxymesterone; methandrostenolol; MENT; precursors capable of liberatingthese androgens when used in the present method and mixtures thereof.More preferably the androgenic component is selected from the groupconsisting of DBEA, testosterone esters, *androstenedione, precursorscapable of liberating these androgens when used in the present methodand mixtures thereof. Most preferably the androgenic component isselected from the group consisting of dehydroepiandrosterone, esters oftestosterone and mixtures thereof.

[0076] Preferably the testosterone esters employed in the present methodcomprise an acyl group which comprises at least 6, more preferably from8-20 and preferably 9-13 carbon atoms. Most preferably the androgensused in the present method are DHEA and/or testosterone undecanoate.These androgens offer the advantage that they can effectively be used inoral dosage units.

[0077] It is noted that, for instance, DHEA, testosterone undecanoateand androstenedione are precursors of testosterone and that saidprecursors per se exhibit virtually no affinity for androgen receptorsin the female body. The effectiveness of the androgens within the methodof the invention is determined by their functionally active form, whichmay well be different from the form in which they are administered.

[0078] In the present method the androgen is preferably provided in anamount equivalent to an oral dosage of at least 5 mg DHEA, which isequivalent to an oral dosage of at least i mg testosterone undecanoate.More preferably the androgen is provided in an amount which isequivalent to an oral dosage of a least 10 mg DBEA, most preferably ofat least 20 mg DHEA. Usually the androgen dosage employed will notexceed the equivalent of an oral dosage of 250 mg DHEA, which isequivalent to an oral dosage of 50 mg testosterone undecanoate.Preferably the androgen is administered in a dosage which does notexceed the equivalent of an oral dosage of 120 mg DHEA, more preferablyit does not exceed the equivalent of an oral dosage 60 mg DHEA.

[0079] The present invention is further illustrated by the followingexamples, which, however, are not to be construed as limiting. Thefeatures disclosed in the foregoing description, in the followingexamples and in the claims may, both separately and in any combinationthereof, be material for realising the invention in diverse formsthereof

EXAMPLES Example 1

[0080] Vaginal cornification was chosen as a tissue-specific andestrogen-sensitive endpoint to determine the estrogenicity of estetrol(E4), after both oral and subcutaneous administration, in hypoestrogenicrats. 17α-ethinylestradiol (BE), 17β-estradiol (E2) and vehicle (10%ethanol/sesame oil) served as controls in these bioassays.

[0081] Uterine weight increase in the rat is more commonly used as ameasure of estrogenicity. However, uterine weight also responds toprogesterone, testosterone, and other agents not characteristicallyregarded as estrogens. In the early 1920s it was discovered thatfollicular fluid from the pig ovary contained a factor(s) that causedcornification/keratinization of the vaginal epithelium in the rat (Allenand Doisy, 1923, JAMA, 81,.819-821; Allen and Doisy, 1924, Am. J.Physiol., 69, 577-588). The so-called vaginal cornification response inrats subsequently provided a bioassay for testing estrogenicity. Vaginalepithelial cornification/keratinization in ovariectomized rats can beproduced only by compounds considered to be true estrogens (Jones et al,1973, Fert. Steril. 24, 284-291). Vaginal epithelialcornification/keratinization represents, therefore, a highly selectiveendpoint to determine the potency of estrogens (Reel et al., 1996, Fund.Appli. Toxicol. 34, 288-305).

[0082] Adult intact female CD rats were ovariectomized to induceestrogen deficiency. Vaginal lavages were performed daily for seven daysto ensure that the rats demonstrated castrate vaginal smears(predominance of leukocytes in the vaginal smear, and similar inappearance to a diestrous vaginal smear). Castrate vaginal smears areindicative that complete ovanectomy was achieved. Treatment commencedfollowing completion of the 7 days of smearing (day 0=first day ofdosing). Animals were dosed, once daily for 7 consecutive days. Dailyvaginal lavages continued to be obtained for 7 days after dosing wasinitiated in order to detect vaginal cornification, as an indication ofan estrogenic response. A drop of vaginal washings was placed on a glassslide and examined by light microscopy to detect the presence or absenceof cornified epithelial cells. Vaginal lavages were obtained prior todosing on days 0-6 and prior to necropsy on day 7.

[0083] The vaginal cornification bioassay was performed in order todetermine the estrogenic profile of E4 when given subcutaneously (sc) toovariectomized adult rats. E2 was used as a positive control. Thevehicle (10% ethanol/sesame oil) served as the negative control.Steroids were dissolved in absolute ethanol and then brought to thefinal concentration with sesame oil (10% ethanol in sesame oil). Avaginal estrogenic response occurred in 8/8 rats by day 2 and persistedthrough day 7 in rats injected sc with 50 μg/kg/day E2 for 7 days (Table1). Animals treated with the vehicle did not exhibit vaginal epithelialcornification (Table 1). The onset of vaginal epithelial cornificationwas dose-dependent in rats injected sc with 0.1, 0.3, 1.0, and 3.0mg/kg/day E4 and started at the same day of treatment (Day 2) asobserved for E2 (Table 1). At 0.1 mg/kg/day E4 already 4/8 rats and at0.3 mg/kg/day E4 even 7/8 rats exhibited a vaginal estrogenic responseby day 7. At 1.0 and 3.0 mg/kg/day E4 all rats showed a vaginalestrogenic response by day 7 (Table 1). TABLE 1 Vaginal estrogenicresponse in ovariectomized rats treated subcutaneously (sc) with17β-estradiol (E2) or estetrol (E4). Data are expressed as the number ofrats showing vaginal cornification over the number of rats (ratio)treated. Number of Rats Exhibiting Estrogenic Response/ Number of RatsTreated Treatment Dosing Day of Study Group route Day 0 Day 1 Day 2 Day3 Day 4 Day 5 Day 6 Day 7 0.05 mg/kg/day sc 0/8 0/8 8/8 8/8 8/8 8/8 8/88/8 E2 Vehicle sc 0/8 0/8 0/8 0/8 0/8 0/8 0/8 0/8 Control  0.1 mg/kg/daysc 0/8 0/8 0/8 1/8 1/8 4/8 3/8 4/8 E4  0.3 mg/kg/day sc 0/8 0/8 1/8 5/87/8 6/8 7/8 7/8 E4  1.0 mg/kg/day sc 0/8 0/8 1/8 6/8 8/8 7/8 8/8 8/8 E4 3.0 mg/kg/day sc 0/8 0/8 3/8 8/8 8/8 8/8 8/8 8/8 E4

[0084] The vaginal cornification bioassay was performed in order todetermine the estrogenic profile of E4 when given orally (po) toovariectomized adult rats. EE was used as a positive control. Thevehicle (10% ethanol/sesamne oil) served as the negative control.Steroids were dissolved in absolute ethanol and then brought to thefinal concentration with sesame oil (10% ethanol in sesame oil). Avaginal estrogenic response occurred in all rats (8/8) given 50μg/kg/day EE po by day 7 (Table 2). Similarly, vaginal epithelialcornification was observed in all rats (8/8) treated po with either 0.1,0.3, 1.0, or 3.0 mg/kg/day E4 by day 7 (Table 2whereas animals treatedwith the vehicle did not exhibit vaginal epithelial cornification (0/8).Surprisingly, even in rats given relatively low doses of E4 (e.g. 0.1mg/kg/day), the onset of vaginal cornification (defined as the amount ofanimals responding at days 1-3 of the study) was faster in po-4treated(Table 2)than in sc-treated animals (Table 1)), demonstrating estetrol'ssuperb bioavailability characteristics after oral administration TABLE 2Vaginal estrogenic response in ovariectomized rats treated orally (po)with 17α-ethinyl estradiol (EE) or estetrol (E4). Data are expressed asthe number of rats showing vaginal cornification over the number of rats(ratio) treated. Number of Rats Exhibiting Estrogenic Response/ Numberof Rats Treated Treatment Dosing Day of study Group route Day 0 Day 1Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 0.05 mg/kg/day po 0/8 1/8 3/8 8/88/8 8/8 8/8 8/8 EE Vehicle po 0/8 0/8 0/8 0/8 0/8 0/8 0/8 0/8 Control (2ml/kg/day)  0.1 mg/kg/day po 0/8 0/8 1/8 7/8 8/8 8/8 8/8 8/8 E4  0.3mg/kg/day po 0/8 0/8 1/8 7/8 8/8 8/8 8/8 8/8 E4  1.0 mg/kg/day po 0/80/8 4/8 8/8 8/8 8/8 8/8 8/8 E4  3.0 mg/kg/day po 0/8 0/8 6/8 8/8 8/8 8/88/8 8/8 E4

Example 2

[0085] To evaluate the oral (po) and subcutaneous (sc) bioavailabilityof estetrol (E4) and to determine the elimination half-life, single dosestudies were performed in female Sprague Dawley rats followed byfrequent blood sampling over a 24 hours interval.

[0086] Female Sprague Dawley rats were equipped with a permanent silaticheart catheter, as described by Kuipers et al. (19S5? Gastroenterology,88, 403-411). Rats were allowed to recover from surgery for 5 days andwere than administered 0.05, 0.5, or 5 mg/kg E4 in 0.5 ml arachis oil.For sc administration, E4 was injected in the neck area using a 1 mlsyringe and 20 g needle. For po administration of E4, rats were lightlyanaesthesized with halothene/N₂O/O₂ and E4 was directly appliedintragastrically using a plastic stomach intubator. Blood samples weresubsequently collected via the heart catheter in heparinized tubes at0.5, 1, 2, 4, 8 and 24 hours. Erytlrocytes were removed bycentrifugation at 5000×g for 10 minutes at 4° C. and blood plasma wasstored at −20° C. After thawing the plasma samples, liquid-liquidextraction (hexane/diethylether) was employed to prepare theE4-containing plasma samples for HPLC analysis (Perkin Elmer 200) andtandem mass spectrometry using a PE Sciex 3000 tandem mass spectrometerand APCI interface. With each sample batch, a calibration curve with 6calibrators was recorded. The calibration curve was calculated usinglinear regression (correlation coefficient>0.98), which permittedquantitation of plasma concentrations. For each rat plasma, sampled atdifferent time intervals, data were collected.

[0087] Plasma E4 concentration data were analysed with “WinNonLin,edition 3.1” and involved pharmacokinetic parameters for C_(max),half-life and AUC₀₋₂₄. Especially, using the lower and intermediate doselevels of 0.05, 0.5 mg/kg, E4 demonstrated an oral bioavailability equalto the bioavailability obtained with sc administration (80-100%). At thehighest dose level tested, 5.0 mg/kg E4, absorption kinetics gave riseto an oral bioavailability approximating 30-60% of sc administered E4.Interestingly, E4 demonstrated a relatively long half-life of 2-3 hours,enabling the detection of bioactive levels of unconjugated E4 at alltime points over a 24 hour interval in the se and po dosing experiments.

Example 3

[0088] Established competitive steroid binding assays were used todetermine the relative binding affinity of estetrol (F4), as compared to17α-ethinylestradiol(EE) and 17β-estradiol (E2), to human EstrogenReceptor (ER) α- and β-forms.

[0089] The method employed was adapted from the scientific literatureand described in detail by Osbourn et al. (1993, Biochemistry, 32,6229-6236). Recombinant human ERα and ERβ proteins were purified fromtransfected Sf9-cells. The in vitro assays involved the use of eitherERα or ERβ proteins and [³H]E2, at a fixed concentration of 0.5 nM, asthe labeled ligand. Recombinant human ERα or ERβ proteins were dissolvedin binding buffer (10 mM Tris-HCL, pH 7.5, 10% glycerol, 1 mM DTT, 1mgg/ml BSA) and duplicate aliquots were then incubated with [³ H]E2 at afinal concentration of 0.5 nM, together with a vehicle control (0.4%DMSO), or the same amount of vehicle containing increasingconcentrations of unlabeled steroid ligands as competitors. Afterincubation for 2 h at 25° C., the unbound ligands were removed and theamounts of [³H]E2 bound to either ERα or ERβ proteins were measured. Theaverage amounts of [³H]E2 bound to either ERα or ERβ proteins at eachconcentration of competitor were used to make inhibition curves. IC50values were subsequently determined by a non-linear, least squaresregression analysis. Inhibition constants (Ki) were calculated using theequation of Cheng and Prusoff (Cheng et al., 1973, Biochem. Pharmacol.,22, 3099-3108), using the measured IC50 of the tested compounds, theconcentration of radioligand employed in the assay, and the historicalvalues for the Kd of the radioligand, which were established as 0.2 nMand 0.13 nM for ERα and ERβ, respectively.

[0090] Biochemical assay results for E4 are presented as the percentinhibition of specific binding in three separate experiments (Table 3).For comparision of binding affinities of E4, EE and E2 to human ERα andERβ proteins, experimentally observed Ki values are shown in Table 4. Ascompared to EE and E2, E4 demonstrates a unique binding profile with astrong preference (400%) for binding to the ERα protein (Table 4). Incontrast, Ki values for ERβ protein are more pronounced for EE and E2steroid ligands (Table 4). TABLE 3 Percent inhibition of specificbinding to ERα and ERβ proteins using E4 as unlabeled steroid ligand and0.5 nM [3H] as labeled competitor. Results of three separate experimentsare shown. Percent inhibition of specific binding in E4 final ERαsteroid binding assay ERβ steroid binding assay concentration Test 1Test 2 Test 3 Test 1 Test 2 Test 3   1 μM 98 nd nd 87 90 95  0.3 μM 9294 101 74 74 77  0.1 μM 83 85 86 56 54 50 0.03 μM 64 66 63 19 25 30   10nM 43 32 28 nd nd nd   3 nM 26 17 11 nd nd nd

[0091] Table 4: Experimentally determined inhibition constants (Ki) forestetrol (E4), 17α-ethinylestradiol (EE) and 17β-estradiol (E2), tohuman ERα and ERβ proteins. Relative preference for binding to ERαprotein is also shown. Relative ERα/ERβ Steroid ligands Ki ERα (nM) KiERβ (nM) preference(%) EE 0.23 0.025 11 E2 0.21 0.015 7 E4 4.9 19 400

Example 4

[0092] An established competitive steroid-binding assay (Hammond andLahteenmaid. 1983.

[0093] Clin Chem Acta 132:101-1 l0)was used to determine the relativebinding affinity of estetrol (E4), 17α-ethinylestradiol(EE2),17β-estradiol (E2), testosterone (T)and 5α-dihydrotestosterone (DHT) forhuman sex Hormone Binding Globulin (SHBG).

[0094] Human SHBG was purified from transgenic mouse serum, as describedpreviously (Avvakumov G V et al., 2000. J Biol Chem 275: 25920-25925).The human SHBG prepared in this way was assessed to be >99% pure bypolyacrylamide gel electrophoresis under denaturing conditions. Itssteroid-binding characteristics are indistinguishable from SHBG in humanserum (Avvakumov G V et al., 2000. J Biol Chem 275: 25920-25925). The invitro assay involved the use of the purified human SHBG and [³H]DHT or[³H]estradiol as labeled ligands. Human SHBG was treated for 30 min atroom temperature with a dextran-coated charcoal (DCC) suspension inphosphate buffered saline (PBS) to remove any steroid ligand.

[0095] After centrifugation (2,000×g for 10 min) to sediment the DCC,the supernatant containing the human SHBG was diluted in PBS to aconcentration of 1 nM based on its steroid binding capacity.

[0096] Duplicate aliquots (100 μl) of this human SHBG solution were thenincubated with an equal volume of either [³H]DHT or [³H]estradiol at 10nM, together with 100 μl of PBS alone or the same amount of PBScontaining increasing concentrations of unlabeled steroid ligands ascompetitors in polystyrene test tubes. After incubation for 1 h at roomtemperature the reaction mixtures were placed in an ice bath for afurther 15 min. Aliquots (600 μl) of an ice cold suspension of DCC werethen added to each tube, and after a brief 2 seconds mixing, each tubewas incubated in an ice bath for either 10 min or 5 min depending onwhether [³H]DHT or [³H]estradiol were being used as labeled ligands,respectively. The unbound ligands adsorbed to DCC were then removed bycentrifugation (2,000×g for 15 min at 4 C), and the amounts of[³H]labeled ligands bound to SHBG were counted in 2 ml ACS scintillationcocktail using in liquid scintillation spectrophotometer. The averageamounts of [³H]labeled ligands bound to SHBG at each concentration ofcompetitor (13) were expressed as a percentage of the average amounts of[³H]labeled ligands bound to SHBG in the absence of competitor (B₀), andwere plotted against the concentration of competitor in each assay tube.The results of the competitive binding assays are depicted in FIG. 1.

[0097] FIG. 1: Competitive displacement of [³H]DHT (panel A) and[³H]estradiol (panel B) from the human sex hormone-binding globulinsteroid binding site. The unlabeled steroid ligands used as competitorswere as follows: estetrol (E4), 17α-ethiylestradiol (EE2), 17β-estradiol(E2), testosterone (T) and 5α-dihydrotestosterone (DHT)

[0098] As is clearly apparent from these competitive binding assays,estetrol does not bind at all to human SHBG when tested with either[³H]DHT or [³H]estradiol as labeled ligands. This is in marked contrastwith reference steroids ethinylestradiol, 17β-estradiol, testosteroneand 5α-dihydrotestosterone, which, in this order, show an increasedrelative binding affinity for human SHBG. Importantly, estetrol bindingto SHBG was negligible when compared with the other estrogens tested,ethinylestradiol and 17β-estradiol.

Example 5

[0099] Dosage Units for Oral Administrations

[0100] The present estrogenic components may suitably be processed,together with additives, excipients and/or flavoring agents customary ingalenic pharmacy, in accordance with the conventional methods into theusual forms of administration. For oral administration, suitable are, inparticular, tablets, dragees, capsules, pills, suspensions, orsolutions.

[0101] Estetrol tablets: 1,000 tablets of 185 mg, containing 1.5 mgestetrol, are produced from the following formulation: Estetrol 1.500 gPolyvinylpyrrolidone (Kollidon 25 ® ex BASF) 13.500 g  Lactose 135.795g  Microcrystalline cellulose (Avicel PH 101 ®) 26.250 g  Glycerylpalmitostearate (Precirol ®) 2.775 g Anhydrous colloidal silica (Aerosil200 ®) 1.000 g Crospovidone (Polyplasdone XL ®) 4.000 g Coloring agent0.180 g

Example 6

[0102] Drug Delivery System for Intranasal Administration

[0103] Suitable nontoxic pharmaceutically acceptable carriers for use ina drug delivery * system for intranasal administration of the presentestogenic component will be apparent to those skilled in the art ofnasal pharmaceutical formulations. For those not skilled in the art,reference is made to “Remington's Pharmaceutical Sciences”, 4th edition,1970. Obviously, the choice of suitable carriers will depend on theexact nature of the particular nasal dosage form desired, e.g. whetherthe estrogenic component is to be formulated into a nasal solution (foruse as drops or as a spray), nasal microspheres, a nasal suspension, anasal ointment or a nasal gel, as well as on the identity of theestrogenic component.

[0104] Examples of the preparation of typical nasal compositions are setforth below.

[0105] Nasal Solution

[0106] 5 mg of estetrol is combined with 10 mg of Tween 80. That mixtureis then combined with a quantity of isotonic saline sufficient to bringthe total volume to 50 ml. The solution is sterilised by being passedthrough a 0.2 micron Millipore filter.

[0107] Nasal Gel

[0108] 250 ml of isotonic saline are heated to 80° C. and 1.5 g ofMethocel are added, with stirring. The resultant mixture is allowed tostand at room temperature for 2 hours.

[0109] Then, 10 mg of estetrol are mixed together with 10 mg of Tween80. The estetrol/Tween mixture and a quantity of isotonic salinesufficient to bring the total volume to 500 ml were added to the gel andthoroughly mixed.

Example 7

[0110] A clinical study is conducted in 40 postmenopausal women who arenot using hormone replacement therapy and who do not suffer from vaginalatrophy or dyspareunia. J-n a baseline cycle, coitus frequency andsexual satisfaction (female orgasm) are recorded.

[0111] Each participant receives blinded medication in 2 differentlylabeled bottles, filled with tablets. One bottle comprises tablets thatcontain 2 mg estetrol, whilst the other bottle contains identicalplacebo tablets. The participants are allowed to choose from whichbottle -to take a tablet, but are instructed not to use more than 1tablet per 24 hours and not more than 2 tablets a week. The totalduration of the study is 4 months.

[0112] It is found that during the study participants use significantlymore estetrol containing tablets than placebo's. In addition, analysisof the data shows that women who mainly used estetrol containing tabletsreport improved libido and sexual enjoyment in comparison to baseline.

[0113] Consequently, it can be concluded that oral administration of 2mg estetrol leads to an improvement of libido and sexual enjoyment insome of these users, whilst no undesirable side-effects are reported.

1. Use of an estrogenic component in the manufacture of a pharmaceuticalcomposition for use in a method of increasing libido in a woman, saidmethod comprising administering to said woman an effective amount of anestrogenic component selected from the group consisting of: substancesrepresented by the following formula

in which formula R₁, R₂, R₃, R₄ independently are a hydrogen atom, ahydroxyl group or an alkoxy group with 1-5 carbon atoms; each of R₅, R₆,R₇ is a hydroxyl group; no more than 3 of R₁, R₂, R₃, R₄ are hydrogenatoms; precursors capable of liberating a substance according to theaforementioned formula when used in the present method; and mixtures ofone or more of the aforementioned substances and/or precursors.
 2. Useaccording to claim 1, wherein R₃ represents a hydroxyl group or analkoxy group.
 3. Use according to claim 1 or 2, wherein at least 3 ofthe groups R₁, R₂, R₃ and R₄ represent hydrogen atoms.
 4. Use accordingto any one of claims 1-3, wherein the precursors are derivatives of thesubstances represented by the formula of claim 1, wherein the hydrogenatom of at least one of the hydroxyl groups in said formula has beensubstituted by an acyl radical of a hydrocarbon carboxylic, sulfonic orsulfamic acid of 1-25 carbon atoms; tetrahydrofuranyl;tetrahydropyranal; or a straight or branched chain glycosidic residuecontaining 1-20 glycosidic units per residue.
 5. Use according to anyone of claims 1-4, wherein the method comprises the oral, transdermal,intranasal, rectal, pulmonary, buccal, subcutaneous, intravaginal orintra-uterine administration of the estrogenic component.
 6. Useaccording to claim 5, wherein the method comprises oral or intranasaladministration.
 7. Use according to-any one of claims 1-6, wherein theestrogenic component is administered in an amount effective to achieve ablood serum concentration of at least 1 nanogram, preferably of at least10 nanogram per litre.
 8. Use according to any one of claims 1-7,wherein the estrogenic component is administered in a dosage of at least1 μg per kg of bodyweight, preferably of at least 5 μg per kg ofbodyweight.
 9. Use according to any one of claims 1-8, wherein theestrogenic component is co-administered with a progestogenic component.10. Use according to any one of claims 1-9, wherein the estrogeniccomponent is co-administered with an androgenic component.